The histamine receptors, H1, H2 and H3 are well-identified forms. The H1 receptors are those that mediate the response antagonized by conventional antihistamines. H1 receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. A well-known antagonist of H1 receptors is loratadine, commercially available under the tradename CLARITIN(copyright) from Schering-Plough Corporation, Madison, N.J. Through H2 receptor-mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.
H3 receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H3 receptor activation by histamine attenuates nonepinephrine outflow to resistance and capacitance vessels, causing vasodilatation.
U.S. Pat. No. 4,767,778 (Arrang et al.) discloses certain imidazoles that behave as agonists of the H3 receptors in rat brain. European Patent Application No. 0 420 396 A2 (Smith Kline and French Laboratories Limited) and Howson et al. (Bioorg. and Med. Chem. Letters, (1992), Vol. 2 No.1, pp. 77-78) describe imidazole derivatives having an amidine group as H3 agonists. Van der Groot et al. (Eur. J. Med. Chem. (1992) Vol. 27, pp. 511-517) describe isothiourea analogs of histamine as potent agonists or antagonists of the histamine-H3 receptor, and these isothiourea analogs of histamine overlap in part with those of the two references cited above. Clapham et al. [xe2x80x9cAbility of Histamine-H3 Receptor Antagonists to Improve Cognition and to Increase Acetylcholine Release in vivo in the Ratxe2x80x9d, British Assn. for Psychopharmacology, July 25-28 (1993), reported in J. Psychopharmacol. (Abstr. Book), A17] describe the ability of histamine-H3 receptor antagonists to improve cognition and to increase release of acetylcholine in vivo in the rat. Clapham et al. [xe2x80x9cAbility of the selective Histamine-H3 Receptor Antagonist Thioperamide to improve Short-term Memory and Reversal Learning in the Ratxe2x80x9d, Brit. J. Pharm. Suppl., 1993, 110, Abstract 65P] present results showing that thioperamide can improve short-term memory and reversal learning in the rat and implicate the involvement of H3 receptors in the modulation of cognitive function. Yokoyama et al.. [xe2x80x9cEffect of Thioperamide, a Histamine-H3 Receptor Antagonist, on Electrically Induced Convulsions in Micexe2x80x9d, Eur. J. Pharmacol., (1 993), Vol. 234, pp. 129-133] report how thioperamide decreased the duration of each phase of convulsion and raised the electroconvulsive threshold, and go on to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures. International Patent Publication No. WO 9301812-A1 (SmithKline Beecham PLC) describes the use of S-[3-(4(5)-imidazolyl)propyl]isothiourea as a histamine-H3 antagonist, especially for treating cognitive disorders, e.g. Alzheimer""s disease and age-related memory impairment. Schlicker et al. [xe2x80x9cNovel Histamine-H3 Receptor Antagonists: Affinities in an H3 Receptor Binding Assay and Potencies in Two Functional H3 Receptor Modelsxe2x80x9d, British J. Pharmacol., (1994), Vol. 112, 1043-1048] describe a number of imidazolylalkyl compounds wherein the imidazolylalkyl group is bonded to a guanidine group, an ester group, an amide group, a thioamide group and a urea group, and compared these to thioperamide. Leurs et al.. [xe2x80x9cThe Histamine-H3-receptor: A Target for Developing New Drugsxe2x80x9d, Progr. Drug Res. (1992), Vol. 39, pp.127-165] and Lipp et al.. [xe2x80x9cPharmacochemistry of H3-receptorsxe2x80x9d in The Histamine Receptor, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pp. 57-72] review a variety of synthetic H3 receptor antagonists, and Lipp et al. (ibid.) have proposed the necessary structural requirements for an H3 receptor antagonist.
WO 95/14007 claims H3 receptor antagonists of the formula 
wherein A, m, n, R1 and R2 are defined therein. The compounds are disclosed as being useful for treating various disorders, in particular such caused by allergy-induced responses.
WO 93/12093 discloses imidazolylmethyl piperazines and diazepines as H3 antagonists. U.S. patent application, Ser. No. 08/965,754, filed Nov. 7, 1997, discloses imidazolylalkyl substituted heterocyclic ring compounds as H3 receptor antagonists. U.S. patent application, Ser. No. 08/966,344, filed Nov. 7, 1997, discloses phenylalkylimidazoles as H3 receptor antagonists.
WO 96/29315 (PCT/FR96/00432) discloses certain N-imidazolylalkyl compounds containing phenyl moieties attached.
Also disclosing H3 receptor antagonists are: H. Stark et al, Eur. J. of Pharmaceutical Sciences (1995) 3, 95-104; H. Stark et al, J. Med. Chem., (1996) 39, 1157-1163; H. Stark et al, Arch. Pharm. Pharm. Med. Chem., (1998) 331, 211-218; and A. Sasse et al, Bioorganic and Medicinal Chem., (2000) 8, 1139-1149.
Reference is also made to J. R. Bagley et al.. Journal of Medicinal Chemistry, (1991), Vol. 34, 827-841, which discloses, among others, N-(imidazolylalkyl) substituted cyclic amine compounds useful as analgesics such as the amine compound with the formula: 
Pending U.S. patent application, Ser. No. 09/173,642, filed Oct. 16, 1998 (R. Wolin et al.) U.S. Pat. No. 6,133,291, discloses N-(imidazolylalkyl) substituted cyclic amine compounds having H3 antagonist activity.
A. Huls et al., Bioorg. and Med. Chem. Letters, 6 (1996), 2013-2018 disclose imidazole compounds containing diphenyl ether moieties as H3 receptor antagonists. The compounds are additionally disclosed to have H1 receptor antagonist activity. An example compound from that publication is: 
where R1 and R2 are defined therein.
A. Buschauer, J. Med. Chem., 32 (1989), 1963-1970 disclose, among others, H2 receptor antagonists of the type: 
where Ar1 and Ar2 may be phenyl and/or pyridyl. EPO 448,765 A1 (published Mar. 30, 1990) discloses neuropeptide-Y antagonist imidazoles of the type: 
where Ar1 and Ar2 may be phenyl and/or pyridyl.
WO 98-58646 (assigned to Novo Nordisk A/S) discloses somatostatin SSTR4 receptor antagonist compounds of the type: 
wherein m is 2-6; n is 1-3; p is 1-6; R1 and R2 are independently H or C1-C6 alkyl optionally substituted with halogen, amino, hydroxy, alkoxy or aryl; X is S, O, NH, NCOPH or N(CN); A is aryl optionally substituted with halogen, amino, hydroxy, nitro, C1 -C6 alkyl, C1-C6 alkoxy, or aryl; and B and D are independently aryl optionally substituted with halogen, a mino, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, or aryl.
Compounds have been reported in the literature as having activity against both H1 and H2 receptors, i.e. dual antagonists against H1 and H2 receptors. Thus, for example, F. Schulze et al., European J. of Pharmaceutical Sciences, 6 (1998), 177-186 report combined H1/H2 receptor antagonists. Other references in this category include F. Schulze et al., Arch. Pharm. (Weinheim), 327 (1994), 455-462; C. Wolf et al., Arch. Pharm. Pharm. Med. Chem., 329 (1996), 87-94; and C. Wolf et al., European J. of Pharmaceutical Sciences, 6 (1998),177-186. Non-imidazole histamine H3 ligands, particularly substituted benzothiazole derivatives as H3 antagonists and H1 blocking activities have been reported by K. Walczynski et al, II Farmaco, 54 (1999), 684-694.
It would be useful to have compounds which are therapeutically effective as antagonists of both the H1 and H3 histamine receptors. The only such reported activity has been through a combination of two different chemical entities, one showing activity against H1 receptors and the other showing activity against H3 receptors. Thus, for example, U.S. Pat. No.5,869,479 (issued Feb. 9, 1999 to Schering Corporation) discloses the combination of a histamine-H1 receptor antagonist and a histamine-H3 receptor antagonist for the treatment of allergy-induced airway responses.
Pending provisional patent application, Ser. No.60/234,040, filed Sep. 20, 2000, discloses novel imidazole compounds having H3 as well as dual H1 and H3 antagonist activity. The compounds disclosed therein have general formula in which an imidazole is linked to two cyclic moieties via intermediary moiety or moieties which intermediary moiety or moieties are acyclic.
Pending provisional patent application, Ser. No. 60/234,039, filed Sep. 20, 2000, discloses novel imidazole compounds having H3 as well as dual H1 and H3 antagonist activity. The compounds disclosed therein have general formula in which an imidazole is linked to two cyclic moieties via intermediary moiety or moieties which intermediary moiety or moieties are acyclic..
Pending provisional patent application, Ser. No. 60/234,053, filed Sep. 20, 2000, discloses novel imidazole compounds having H3 as well as dual H1 and H3 antagonist activity. The compounds disclosed therein have general formula in which an imidazole is linked to a tricyclic moiety via intermediary moiety or moieties at least one of which intermediary moiety or moieties is a cyclic moiety.
It would be a welcome contribution to the art to have novel substituted imidazole compounds.
It would be useful to have novel imidazoles showing activity against H3 receptors.
It would be useful to have novel substituted imidazoles showing activity against both H1 and H3 receptors.
It would be useful to have novel substituted imidazoles showing activity against both H1 and H3 receptors.
This invention provides just such a contribution by providing novel substituted imidazole compounds having H3 as well as dual H1 and H3 antagonist activity.
In one embodiment, this invention provides novel substituted imidazole compounds having H3 antagonist activity as well as dual H1 and H3 antagonist activity. The inventive compounds are substituted imidazoles wherein the imidazole is linked to a tricyclic moiety via intermediary moiety or moieties which intermediary moiety or moieties are acyclic. The compounds have the general structure shown in Formula I: 
wherein
G is selected from the group consisting of xe2x80x94(CH2)vxe2x80x94NR3xe2x80x94, xe2x80x94(CH2)vxe2x80x94Oxe2x80x94, (CH2)vxe2x80x94S(O)zxe2x80x94, xe2x80x94(CH2)vxe2x80x94NR3xe2x80x94C(NR4)xe2x80x94NR3xe2x80x94, xe2x80x94(CH2)vxe2x80x94Oxe2x80x94C(O)NR3xe2x80x94, xe2x80x94(CH2)vxe2x80x94NR3C(O)NR3xe2x80x94, xe2x80x94(CH2)vxe2x80x94NR3C(O)Oxe2x80x94, xe2x80x94(CH2)vxe2x80x94NR3C(O)xe2x80x94, xe2x80x94(CH2)vC(O)NR3xe2x80x94;
M is a branched or unbranched alkyl group consisting of 1-6 carbon atoms, or a branched or unbranched alkenyl group consisting of 2-6 carbon atoms;
X and Y are independently selected from the group consisting of N, CH or N-oxide;
R1 and R2 may each number 1-4 and are independently selected from the group consisting of H, halogen, lower alkyl, lower alkoxy, polyhalo lower alkoxy, OH, CF3, NH2, NHC(O)alkyl, CN or NO2;
R3 is independently selected from the group consisting of H, lower alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or a group of the formula: 
R4 is selected from the group consisting of H, CN, CO2R5;
R5 is selected from the group consisting of lower alkyl and substituted or unsubstituted benzyl;
R6 is selected from the group consisting of H or lower alkyl;
q is 2-5;
v is 0-6; and
z is 0, 1 or 2.
When used herein, the following terms have the given meanings:
lower alkyl (including the alkyl portions of lower alkoxy)xe2x80x94represents a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms, preferably from 1 to 4;
arylxe2x80x94represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment. Preferred aryl groups include 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl;
cycloalkylxe2x80x94represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, optionally substituted.
heterocyclicxe2x80x94represents, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one O, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl;
halogenxe2x80x94represents fluorine, chlorine, bromine and iodine;
heteroarylxe2x80x94represents a cyclic organic group having at least one O, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2-or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, etc. Preferred heteroaryl groups are 2- , 3- and 4-pyridyl; Such heteroaryl groups may also be optionally substituted.
The term xe2x80x9csubstitutedxe2x80x9d, unless otherwise defined, refers to chemically suitable substitution with moieties such as, for example, alkyl, alkoxy, xe2x80x94CF3, halogen or aryl.
Furthermore, the term xe2x80x9calkylxe2x80x9d, when chemically suitable, also includes alkylene and related moieties. Thus, for example, the above-described definitions for G and V, could also include moieties such as, for example, ethylene, butylene, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94C(=CH2)xe2x80x94, and the like.
Also included in the invention are tautomers, enantiomers and other optical isomers of compounds of Formula I, as well as pharmaceutically acceptable salts and solvates thereof.
A further feature of the invention is pharmaceutical compositions containing as active ingredient a compound of Formula I (or its salt, solvate or isomers) together with a pharmaceutically acceptable carrier or excipient.
The invention also provides methods for preparing compounds of Formula I, as well as methods for treating diseases such as, for example, inflammation, allergy, diseases of the GI-tract, cardiovascular disease, or disturbances of the central nervous system as well as allergy-induced airway (e.g., upper airway) responses, nasal congestion and obesity. The methods for treating comprise administering to a mammalian patient (including humans and animals) suffering from said disease or diseases a therapeutically effective amount of a compound of Formula I, or pharmaceutical compositions comprising a compound of Formula I.